Hydrophobic core packing in the SH3 domain folding transition state

2002 ◽  
Vol 9 (2) ◽  
pp. 126-130 ◽  
Author(s):  
Julian G.B. Northey ◽  
Ariel A. Di Nardo ◽  
Alan R. Davidson
Keyword(s):  
Transition State ◽  
Sh3 Domain ◽  
Hydrophobic Core ◽  
Core Packing

scholarly journals Structural Determinants of Coiled Coil Mechanics

2019 ◽  
Author(s):  
Patricia Lopez-Garcia ◽  
Melis Goktas ◽  
Ana E. Bergues-Pupo ◽  
Beate Koksch ◽  
Daniel Varon Silva ◽  
...  
Keyword(s):  
Transition State ◽  
Single Molecule ◽  
Mechanical Stability ◽  
Coiled Coil ◽  
Building Blocks ◽  
Shear Loading ◽  
Hydrophobic Core ◽  
Structural Determinants ◽  
Helix Propensity ◽  
Core Packing

The natural abundance of coiled coil (CC) motifs in the cytoskeleton and the extracellular matrix suggests that CCs play a crucial role in the bidirectional mechanobiochemical signaling between cells and the matrix. Their functional importance and structural simplicity has allowed the development of numerous applications, such as protein-origami structures, drug delivery systems and biomaterials. With the goal of establishing CCs as nanomechanical building blocks, we investigated the importance of helix propensity and hydrophobic core packing on the mechanical stability of 4-heptad CC heterodimers. Using single-molecule force spectroscopy, we show that both parameters determine the force-induced dissociation in shear loading geometry; however, with different effects on the energy landscape. Decreasing the helix propensity lowers the transition barrier height, leading to a concomitant decrease in the distance to the transition state. In contrast, a less tightly packed hydrophobic core increases the distance to the transition state. We propose that this sequence-structure-mechanics relationship is evolutionarily optimized in natural CCs and can be used for tuning their mechanical properties in applications.

scholarly journals High-resolution structure of an α-spectrin SH3-domain mutant with a redesigned hydrophobic core

2010 ◽  
Vol 66 (9) ◽  
pp. 1023-1027 ◽  
Author(s):  
Ana Cámara-Artigas ◽  
Monserrat Andújar-Sánchez ◽  
Emilia Ortiz-Salmerón ◽  
Celia Cuadri ◽  
Eva S. Cobos ◽  
...  
Keyword(s):  
Structural Information ◽  
Sh3 Domain ◽  
Hydrophobic Core ◽  
Orthorhombic Space Group ◽  
Cell Parameters ◽  
High Resolution Structure ◽  
Model Protein ◽  
Distal Loop ◽  
Modular Domain ◽  
The Stability

The α-spectrin SH3 domain (Spc-SH3) is a small modular domain which has been broadly used as a model protein in folding studies and these studies have sometimes been supported by structural information obtained from the coordinates of Spc-SH3 mutants. The structure of B5/D48G, a multiple mutant designed to improve the hydrophobic core and as a consequence the protein stability, has been solved at 1 Å resolution. The crystals belonged to the orthorhombic space groupP212121, with unit-cell parametersa= 24.79,b= 37.23,c= 62.95 Å. This mutant also bears a D48G substitution in the distal loop and this mutation has also been reported to increase the stability of the protein by itself. The structure of the B5/D48G mutant shows a highly packed hydrophobic core and a more ordered distal loop compared with previous Spc-SH3 structures.

scholarly journals Conserved patterns and interactions in the unfolding transition state across SH3 domain structural homologues

2020 ◽  
Vol 30 (2) ◽  
pp. 391-407
Author(s):  
Cullen Demakis ◽  
Matthew C. Childers ◽  
Valerie Daggett
Keyword(s):  
Transition State ◽  
Sh3 Domain ◽  
Structural Homologues

scholarly journals Molecular dynamics simulations suggest stabilizing mutations in a de novo designed α/β protein

2019 ◽  
Vol 32 (7) ◽  
pp. 317-329
Author(s):  
Matthew Gill ◽  
Michelle E McCully
Keyword(s):  
Molecular Dynamics ◽  
Secondary Structure ◽  
Surface Area ◽  
De Novo ◽  
Md Simulations ◽  
Solvent Accessible Surface Area ◽  
Hydrophobic Core ◽  
Design Strategies ◽  
Major Interest ◽  
Core Packing

Abstract Designing functional proteins that can withstand extreme heat is beneficial for industrial and protein therapeutic applications. Thus, elucidating the atomic-level determinants of thermostability is a major interest for rational protein design. To that end, we compared the structure and dynamics of a set of previously designed, thermostable proteins based on the activation domain of human procarboxypeptidase A2 (AYEwt). The mutations in these designed proteins were intended to increase hydrophobic core packing and inter-secondary-structure interactions. To evaluate whether these design strategies were successfully deployed, we performed all-atom, explicit-solvent molecular dynamics (MD) simulations of AYEwt and three designed variants at both 25 and 100°C. Our MD simulations agreed with the relative experimental stabilities of the designs based on their secondary structure content, Cα root-mean-square deviation/fluctuation, and buried-residue solvent accessible surface area. Using a contact analysis, we found that the designs stabilize inter-secondary structure interactions and buried hydrophobic surface area, as intended. Based on our analysis, we designed three additional variants to test the role of helix stabilization, core packing, and a Phe → Met mutation on thermostability. We performed the additional MD simulations and analysis on these variants, and these data supported our predictions.

Transition state of a SH3 domain detected with principle component analysis and a charge-neutralized all-atom protein model

2006 ◽  
Vol 64 (4) ◽  
pp. 883-894 ◽  
Author(s):  
Daisuke Mitomo ◽  
Hironori K. Nakamura ◽  
Kazuyoshi Ikeda ◽  
Akihiko Yamagishi ◽  
Junichi Higo
Keyword(s):  
Transition State ◽  
Principle Component Analysis ◽  
Component Analysis ◽  
Sh3 Domain ◽  
Principle Component ◽  
Protein Model ◽  
A Charge

Pressure- and temperature-induced unfolding studies: thermodynamics of core hydrophobicity and packing of ribonuclease A

2006 ◽  
Vol 387 (3) ◽  
pp. 285-296 ◽  
Author(s):  
Josep Font ◽  
Antoni Benito ◽  
Joan Torrent ◽  
Reinhard Lange ◽  
Marc Ribó ◽  
...  
Keyword(s):  
Hydrophobic Interactions ◽  
Rnase A ◽  
Van Der Waals Interactions ◽  
Hydrophobic Core ◽  
Experimental Conditions ◽  
Unfolded State ◽  
Different Temperatures ◽  
Methylene Groups ◽  
The Stability ◽  
Core Packing

Abstract In this work we demonstrate that heat and pressure induce only slightly different energetic changes in the unfolded state of RNase A. Using pressure and temperature as denaturants on a significant number of variants, and by determining the free energy of unfolding at different temperatures, we estimated the stability of variants unable to complete the unfolding transition owing to the experimental conditions required for pressure experiments. The overall set of results allowed us to map the contributions to stability of the hydrophobic core residues of RNase A, with the positions most critical for stability being V54, V57, I106 and V108. We also show that the stability differences can be attributed to both hydrophobic interactions and packing density with an equivalent energetic magnitude. The main hydrophobic core of RNase A is tightly packed, as shown by the small-to-large and isosteric substitutions. In addition, we found that large changes in the number of methylene groups have non-additive positive stability interaction energies that are consistent with exquisite tight core packing and rearrangements of van der Waals' interactions in the protein interior, even after drastic deleterious substitutions.

A Thermodynamic and Kinetic Analysis of the Folding Pathway of an SH3 Domain Entropically Stabilised by a Redesigned Hydrophobic Core

2003 ◽  
Vol 328 (1) ◽  
pp. 221-233 ◽  
Author(s):  
Eva S Cobos ◽  
Vladimir V Filimonov ◽  
Maria Cristina Vega ◽  
Pedro L Mateo ◽  
Luis Serrano ◽  
...  
Keyword(s):  
Kinetic Analysis ◽  
Sh3 Domain ◽  
Folding Pathway ◽  
Hydrophobic Core

scholarly journals The osmolyte trimethylamine-N -oxide stabilizes the Fyn SH3 domain without altering the structure of its folding transition state

2009 ◽  
Vol 18 (3) ◽  
pp. 526-536 ◽  
Author(s):  
Sung Lun Lin ◽  
Arash Zarrine-Afsar ◽  
Alan R. Davidson
Keyword(s):  
Transition State ◽  
Sh3 Domain
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